Abstract
The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers–Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions.
Key points
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POLG encodes the catalytic subunit of DNA polymerase γ, the enzyme responsible for replicating the mitochondrial DNA (mtDNA).
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Mutations in POLG are associated with a clinical continuum of heterogeneous syndromes, ranging from infantile-onset epilepsies and liver failure to late-onset ophthalmoplegia and muscle weakness.
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POLG mutations are a frequent cause of mitochondrial disease, particularly mitochondrial epilepsy, polyneuropathy, ataxia and progressive external ophthalmoplegia.
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POLG mutations can lead to depletion of the mtDNA and/or accumulation of multiple mtDNA deletions.
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To a limited extent, clinical phenotypes correlate with the mtDNA phenotype (depletion or deletions).
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No effective disease-modifying therapies are currently available for POLG-related disease, and symptomatic therapies are the mainstay of treatment.
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Acknowledgements
This work was supported by funding from the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (grants ES 065078 and ES 065080) to W.C.C., and from the Great Ormond Street Hospital Children’s Charity Research Leadership Award (V1260), the Lily Foundation, and the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London, UK, to S.R.
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Related links
Human DNA Polymerase Gamma Mutation Database: https://tools.niehs.nih.gov/polg
dbSNP rs113994098: https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=113994098
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Rahman, S., Copeland, W.C. POLG-related disorders and their neurological manifestations. Nat Rev Neurol 15, 40–52 (2019). https://doi.org/10.1038/s41582-018-0101-0
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DOI: https://doi.org/10.1038/s41582-018-0101-0
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